Target genes of β-catenin-T cell-factor lymphoid-enhancer-factor signaling in human colorectal carcinomas
Target genes of β-catenin-T cell-factor lymphoid-enhancer-factor signaling in human colorectal carcinomas
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DOI：
10.1073/pnas.96.4.1603
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发表时间：
1999-02-16
影响因子：
11.1
通讯作者：
Hanski, C
中科院分区：
文献类型：
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作者：
Mann, B;Gelos, M;Hanski, C
腺瘤性结肠息肉病或β-连环蛋白基因的突变导致β-连环蛋白的胞质积累，随后导致β-连环蛋白-T细胞因子/淋巴增强因子复合物的转录活性增加。这一过程似乎在大多数结直肠癌的发展中起着至关重要的作用。为了鉴定由β-连环蛋白过表达激活的基因，我们使用大肠癌细胞系转染β-连环蛋白基因，并寻找在转染子中差异表达的基因。有四种基因受β-连环蛋白过表达的影响;三种过表达的基因编码AP-1转录复合物的两种组分，c-jun和fra-1，以及尿激酶型纤溶酶原激活物受体（uPAR），其转录由AP-1激活。凝胶迁移试验显示β-连环蛋白-T细胞因子/淋巴样增强因子复合物与c-jun和fra-1启动子区的直接相互作用。在原发性结肠癌及其肝转移瘤中，β-连环蛋白表达和uPAR量的伴随增加在mRNA和蛋白水平上都得到了证实。在转染子中，以及在另外分析的结直肠细胞系中，β-连环蛋白的高表达与ZO-1的表达降低相关，ZO-1参与上皮极化。因此，β-连环蛋白的积累间接影响uPAR在体外和体内的表达。与其他改变一起，β-连环蛋白积累可能通过去分化和蛋白水解活性促进结肠癌的发展和进展。
Mutations in the adenomatous polyposis coli or beta-catenin gene lead to cytosolic accumulation of beta-catenin and, subsequently, to increased transcriptional activity of the beta-catenin-T cell-factor/lymphoid-enhancer-factor complex. This process seems to play an essential role in the development of most colorectal carcinomas. To identify genes activated by beta-catenin overexpression, we used colorectal cell lines for transfection with the beta-catenin gene and searched for genes differentially expressed in the transfectants. There are four genes affected by beta-catenin overexpression; three overexpressed genes code for two components of the AP-1 transcription complex, c-jun, and fra-1, and for the urokinase type plasminogen activator receptor (uPAR), whose transcription is activated by AP-1. The direct interaction of the beta-catenin-T cell-factor/lymphoid-enhancer-factor complex with the promoter region of c-jun and fra-1 was shown in a gel shift assay. The concomitant increase in beta-catenin expression and the amount of uPAR was confirmed in primary colon carcinomas and their liver metastases at both the mRNA and the protein levels. High expression of beta-catenin in transfectants, as well as in additionally analyzed colorectal cell lines, was associated with decreased expression of ZO-1, which is involved in epithelial polarization. Thus, accumulation of beta-catenin indirectly affects the expression of uPAR in vitro and in vivo. Together with the other alterations, beta-catenin accumulation may contribute to the development and progression of colon carcinoma both by dedifferentiation and through proteolytic activity.